The High-Throughput Screening Core allows the rapid identification of biologically active chemical scaffolds from libraries containing several thousand discrete chemicals, and potentially containing naturally occurring ones obtained from natural sources such as plants. MSKCC has implemented the creation of a state of the art high throughput screening core facility with modern robotics, custom built screening data management databases for storing and querying data, and setting up strategic collaborations for the supply chemicals and to provide expertise in medicinal chemistry optimization. The facility contains a custom built six meter linear track robotic platform equipped with plate hotels, incubators for cell based assays, bulk liquid dispensers (Multidrops), 384/1536 liquid handlers (Apricot Designs TPS), a Perkin Elmer MicroBeta counter, two Perkin Elmer Victors multi-detection plates readers, two Molecular Device absorbance scanners, and one Amersham Multi-detection imager. Screening data acquisition and management is handled through custom built software named ORIS, which is composed of a chemical registration and inventory function together with an automated data loader for acquisition, analysis and screen data publishing. The compound library will grow to up to 500,000 discrete chemicals from selected commercial vendors and will also contain a wide variety of natural products, some purified and others in extract mixtures pending screening and dereplication to identify and purify the active product(s). The impact of such an infrastructure on the ongoing cancer research will be in the following areas: 1) Chemical cancer biology to discover novel control mechanisms to help further elucidate known or discover novel cancer pathways including control junctions, 2) Novel chemical scaffolds for use as radiotracers for biochemical and metabolic studies in vivo and for use in cancer diagnostics, and 3) the classical drug discovery process in which in vitro and/or cell based targets are screened and the resulting chemical hits are subjected to secondary and high content screens, in order to further optimize their chemical structures and their drug properties, and to show some efficacy against the specific cancer with little or no side effects, making them good drug candidates for the clinic.